♀Dostinex is used for treating disorders associated with high levels of the hormone prolactin, either due to tumors in the pituitary gland or to unknown causes.♀

♀Pharmachologic effect

Dopamine receptor agonist. Cabergoline is a dopaminergic ergoline derivative, characterized by a pronounced and prolonged prolactin-lowering effect. The mechanism of action is associated with direct stimulation of the dopamine D2 receptors of the lactotropic pituitary cells. In doses exceeding those to reduce the level of prolactin in the blood plasma, it has a central dopaminergic effect due to the stimulation of dopamine D2 receptors.

A decrease in the concentration of prolactin in the blood plasma is noted 3 hours after taking the drug and persists for 7-28 days in healthy volunteers and patients with hyperprolactinemia, and up to 14-21 days in women in the postpartum period. Prolactin-reducing action is dose-dependent both in terms of severity and duration of action.

Cabergoline has a strictly selective effect, does not affect the basal secretion of other pituitary and cortisol hormones.

Pharmacological effects of cabergoline, not related to the therapeutic effect, include only a decrease in blood pressure. With a single use of the drug, the maximum hypotensive effect is observed during the first 6 hours and is dose-dependent.

♀Pharmacokinetics

٭Suction and distribution

After oral administration, cabergoline is rapidly absorbed from the gastrointestinal tract. Cmax in plasma is achieved in 0.5-4 hours. Binding to plasma proteins is 41-42%. Css is achieved after 4 weeks of therapy due to prolonged T1 / 2.

Meal does not affect the absorption and distribution of cabergoline.

٭Metabolism

The main product of cabergoline metabolism identified in the urine is 6-allyl-8β-carboxy-ergoline at a concentration of up to 4-6% of the dose taken. The content in the urine of 3 additional metabolites does not exceed 3% of the dose. Metabolism products have a significantly lower effect in suppressing the secretion of prolactin compared to cabergoline.

٭Removal

T1 / 2, estimated by the rate of excretion by the kidneys, is 63-68 h in healthy volunteers and 79-115 h in patients with hyperprolactinemia.

10 days after taking the drug, 18% and 72% of the received dose are detected in the urine and feces, respectively, and the proportion of unchanged cabergoline in the urine is 2-3%.

♀Indications ☞prevention of physiological postpartum lactation;

☞suppression of established postpartum lactation;

☞treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation and galactorrhea;

Lactation prevention: 1 mg (2 tab.) Once on the first day after birth.

Suppression of established lactation: 0.25 mg (1/2 tab.) 2 times / day every 12 hours for 2 days (total dose is 1 mg). In order to reduce the risk of orthostatic hypotension in lactating mothers, a single dose of Dostinex should not exceed 0.25 mg.

Treatment of disorders associated with hyperprolactinemia: the recommended initial dose is 0.5 mg per week in 1 (1 tab.) Or 2 doses (1/2 tab., For example, on Monday and Thursday). Increasing the weekly dose should be carried out gradually – at 0.5 mg with an interval of 1 month to achieve the optimal therapeutic effect. The therapeutic dose is usually 1 mg per week, but can range from 0.25 mg to 2 mg per week. The maximum dose for patients with hyperprolactinemia is 4.5 mg per week.

Depending on tolerance, the weekly dose can be taken once or divided into 2 or more doses per week. The division of the weekly dose into several doses is recommended when prescribing the drug in a dose of more than 1 mg per week.

In patients with hypersensitivity to dopaminergic drugs, the likelihood of side effects can be reduced by starting Dostinex therapy at a lower dose (0.25 mg 1 time per week), followed by a gradual increase until the therapeutic dose is reached. To improve the tolerability of the drug in the event of severe side effects, a temporary dose reduction is possible, followed by a gradual increase, for example, by 0.25 mg per week every 2 weeks.

♀Side effect In clinical studies using Dostinex to prevent physiological lactation (1 mg once) and to suppress lactation (0.25 mg every 12 hours for 2 days), approximately 14% of women had adverse reactions. When using Dostinex for 6 months at a dose of 1-2 mg per week, divided into 2 doses, for the treatment of disorders associated with hyperprolactinemia, the incidence of adverse reactions was 68%. Adverse reactions occurred mainly during the first 2 weeks of therapy and in most cases disappeared as therapy continued or several days after discontinuation of the drug Dostinex. Adverse reactions were usually transient, mild or moderate in severity and dose-dependent. At least once during the course of therapy, severe side effects were observed in 14% of patients; due to adverse reactions, treatment was discontinued in approximately 3% of patients.

The most frequent adverse reactions are presented below.

☁Since the cardiovascular system: heartbeat; rarely, orthostatic hypotension (with prolonged use, the drug has a hypotensive effect); asymptomatic decrease in blood pressure during the first 3-4 days after birth (systolic – more than 20 mm Hg, diastolic – more than 10 mm Hg).

🌞With long-term therapy with the use of the drug Dostinex, deviation from the norm of standard laboratory parameters was rarely observed; in women with amenorrhea, a decrease in hemoglobin level was observed during the first few months after the recovery of menstruation.🌞

♀Contraindications 🍓Hypersensitivity to cabergoline or other components of the drug, as well as to any ergot alkaloids;

🍓dysfunction of the heart and respiration due to fibrous changes or the presence of such conditions in history;

🍓during long-term therapy: anatomical signs of valvular pathology of the heart (such as thickening of the valve leaflet, narrowing of the valve lumen, mixed pathology of narrowing and stenosis of the valve), confirmed by echocardiography (EchoCG), conducted before the start of therapy;

🍓children and adolescents under 16 years of age (safety and efficacy have not been established).

Dostinex should be administered with caution in the following conditions and / or diseases:

🍓arterial hypertension that developed during pregnancy, for example, preeclampsia or postpartum arterial hypertension (Dostinex is prescribed only in cases where the potential benefit from the use of the drug significantly exceeds the possible risk);

🍓severe cardiovascular diseases, Raynaud’s syndrome;

🍓peptic ulcer, gastrointestinal bleeding;

🍓severe liver failure (the use of lower doses is recommended);

🍓severe psychotic or cognitive impairment (including in history);

🍓simultaneous use with drugs that have a hypotensive effect (due to the risk of orthostatic hypotension).

♀Use during pregnancy and lactation Since there have been no controlled clinical trials with the use of the drug Dostinex in pregnant women, the prescription of the drug during pregnancy is possible only in cases of emergency, when the expected benefit to the mother outweighs the potential risk to the fetus.

If pregnancy has occurred on the background of treatment with Dostinex, the feasibility of discontinuing the drug should be considered, also taking into account the benefit / risk ratio.

According to available data, the use of Dostinex in a dose of 0.5-2 mg per week for disorders associated with hyperprolactinemia was not accompanied by an increase in the frequency of miscarriages, premature birth, multiple pregnancy and congenital malformations.

There is no information about the release of the drug in breast milk, however, in the absence of the effect of using the drug Dostinex to prevent or suppress lactation, breastfeeding should be abandoned. For disorders associated with hyperprolactinemia, Dostinex should not be prescribed to mothers who do not want to stop lactation.

♀Application for violations of the liver With caution, use the drug in severe liver failure (lower doses are recommended).

♀Use in children Contraindications: children and adolescents under 16 years of age (safety and efficacy have not been established).

♀Special instructions Before prescribing Dostinex for the purpose of treating disorders associated with hyperprolactinemia, it is necessary to conduct a full study of the function of the pituitary gland.

In addition, the state of the cardiovascular system, including echocardiography, should be assessed in order to detect valvular dysfunction asymptomatic.

As with the use of other ergot derivatives, pleural effusion / pleural fibrosis and valvulopathy were observed in patients after long-term administration of cabergoline. In some cases, patients received prior therapy with dopamine ergotonin agonists. Therefore, Dostinex should not be used in patients with existing signs and / or clinical symptoms of dysfunction of the heart or respiration associated with fibrotic changes or with such a history. The drug should be discontinued if there are signs of the appearance or worsening of blood regurgitation, narrowing of the lumen of the valves or thickening of the valve leaflets.

It was found that ESR increases with the development of pleural effusion or fibrosis. If an unexplained increase in ESR is detected, a chest X-ray is recommended. A study of the concentration of creatinine in the blood plasma and an assessment of renal function can also help in the diagnosis. After discontinuation of Dostinex in patients with pleural effusion / pleural fibrosis or valvulopathy, symptoms improved.

It is not known whether cabergoline can worsen the condition of patients with signs of blood regurgitation. Cabergoline should not be used in the detection of fibrous lesions of the valvular apparatus of the heart.

Fibrotic disorders can develop asymptomatically. In this regard, the condition of patients receiving long-term treatment with cabergoline should be regularly monitored and special attention should be paid to the following symptoms:

☞renal failure or obstruction of the vessels of the ureters or abdominal organs, which may be accompanied by pain in the side or lumbar region and edema of the lower extremities, any swelling or tenderness in the abdominal region, which may indicate the development of retroperitoneal fibrosis;

☞pericardial fibrosis and fibrosis of the valves of the heart often manifest heart failure. In this regard, it is necessary to exclude fibrosis of the valves of the heart (and constrictive pericarditis) at the onset of symptoms of heart failure.

It should regularly monitor the patient’s condition for the development of fibrotic disorders. The first time EchoCG should be performed 3-6 months after the start of therapy. Then this study should be conducted depending on the clinical assessment of the patient’s condition, paying particular attention to the symptoms described above, at least every 6-12 months of therapy.

The need for other monitoring methods (for example, physical examination, including auscultation of the heart, radiography, computed tomography) is assessed individually for each patient.

With increasing doses, patients should be under the supervision of a physician in order to establish the minimum effective dose that provides a therapeutic effect.

After an effective dosing regimen is selected, it is recommended to regularly (once a month) determine the serum prolactin concentration. Normalization of prolactin concentration is usually observed within 2-4 weeks of treatment.

After discontinuation of Dostinex, there is usually a relapse of hyperprolactinemia, however, in some patients persistent inhibition of prolactin concentration is observed for several months. In most women, ovulatory cycles persist for at least 6 months after discontinuation of Dostinex.

Dostinex restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy can occur before menstruation is restored, it is recommended that pregnancy tests be performed at least once every 4 weeks during the amenorrhea period, and after menstruation is restored – every time there is a delay in menstruation for more than 3 days. Women who want to avoid pregnancy should use barrier methods of contraception during treatment with Dostinex, as well as after discontinuation of the drug before repeating anovulation. Women who have become pregnant should be supervised by a physician in order to identify the symptoms of an increase in the pituitary gland in a timely manner, since an increase in the size of existing pituitary tumors is possible during pregnancy.

Dostinex should be administered in lower doses to patients with severe hepatic insufficiency (Child-Pugh class C), who have been given prolonged therapy with the drug. With a single dose of 1 mg in these patients, an increase in AUC was observed compared with healthy volunteers and patients with less severe hepatic insufficiency.

The use of cabergoline causes drowsiness. In patients with Parkinson’s disease, the use of dopamine receptor agonists can cause sudden sleep. In such cases, it is recommended to reduce the dose of the drug Dostinex or discontinue therapy.

Studies on the use of the drug in elderly patients with disorders associated with hyperprolactinemia, was not conducted.

♀Use in Pediatrics

The safety and efficacy of the drug in children and adolescents under 16 years of age has not been established.

Influence on ability to drive motor transport and control mechanisms

Patients taking the drug Dostinex should refrain from driving vehicles and mechanisms and other potentially dangerous activities requiring concentration of attention and speed of psychomotor reactions.

Treatment: should carry out activities aimed at removing the drug (gastric lavage) and to maintain blood pressure. The use of dopamine antagonists is recommended.

♀Drug interaction

Information about the interaction of cabergoline and other ergot alkaloids is absent, therefore the simultaneous use of these drugs during long-term therapy with Dostinex is not recommended.

Since cabergoline has a therapeutic effect by direct stimulation of dopamine receptors, the drug cannot be administered simultaneously with drugs acting as dopamine antagonists (including phenothiazines, butyrophenones, thioxanthenes, metoclopramide), because they can weaken the effect of cabergoline, aimed at reducing the concentration of prolactin.

Like other ergot derivatives, cabergoline cannot be used simultaneously with macrolide antibiotics (for example, with erythromycin), since this can lead to an increase in the system bioavailability of cabergoline.

♀Terms and conditions of storage The drug should be stored out of reach of children at a temperature not exceeding 25 ° C. Shelf life – 2 years.